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Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats.

Davies DR, Olson D, Meyer DL, Scholl JL, Watt MJ, Manzerra P, Renner KJ, Forster GL - Front Behav Neurosci (2016)

Bottom Line: However, this effect was enhanced by the combination of treatments.Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning.The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

View Article: PubMed Central - PubMed

Affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota Vermillion, SD, USA.

ABSTRACT
Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

No MeSH data available.


Related in: MedlinePlus

Serotonin (5-HT) measurements 7 days following stress and/or mTBI, including (A) 5-HTP concentration in the ventral hippocampus, (B) 5-HIAA concentration in the dorsal hippocampus, (C) 5-HT activity in the central amygdala, and (D) 5-HT synthesis in the medial prefrontal cortex.∗ Indicates significant difference from all other groups, while ∗ overlying a bar indicates significant difference between individual groups (p < 0.05).
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Figure 4: Serotonin (5-HT) measurements 7 days following stress and/or mTBI, including (A) 5-HTP concentration in the ventral hippocampus, (B) 5-HIAA concentration in the dorsal hippocampus, (C) 5-HT activity in the central amygdala, and (D) 5-HT synthesis in the medial prefrontal cortex.∗ Indicates significant difference from all other groups, while ∗ overlying a bar indicates significant difference between individual groups (p < 0.05).

Mentions: Changes to serotonin function according to treatment were restricted to the hippocampus (dorsal and ventral), the central amygdala, and the medial prefrontal cortex. Alterations in the concentration of 5-HTP were restricted to the ventral hippocampus [Figure 4A; F(3,43) = 4.304, p = 0.010], with the social defeat + mTBI group having significantly higher 5-HTP than all other groups (SNK, p < 0.027). Similarly, the concentration of 5-HIAA was altered in the dorsal hippocampus [Figure 4B; F(3,44) = 4.677, p = 0.006], with the combined treatment of social defeat and mTBI producing higher 5-HIAA concentrations than all other groups (SNK, p < 0.015). Furthermore there was a significant negative correlation between 5-HIAA levels in the dorsal hippocampus and time in open arms of the EPM for social defeat + mTBI group (correlation coefficient = -0.761; p = 0.017). In the central amygdala, serotonergic activity (5-HIAA/serotonin) was significantly different among treatment groups [Figure 4C; F(3,40) = 3.973, p = 0.014], with social defeat + mTBI rats showing higher serotonergic activity than both sham + control (SNK, p = 0.026) and sham + mTBI (SNK, p = 0.019) groups. However, this particular effect appeared to be driven by exposure to social defeat, as changes to central amygdala serotonergic activity were equivalent in all defeated rats with or without mTBI (SNK, p = 0.197). Serotonin synthesis capacity (serotonin/5-HTP) was only affected in the medial prefrontal cortex [Figure 4D; F(3.40) = 3.453, p = 0.025], with exposure to either mTBI, social defeat, or a combination of these two factors causing reductions in the serotonin/5-HTP ratio compared to control + sham rats (SNK, p = 0.046). There were no differences in either 5-HT concentrations in any brain region assayed (Table 1).


Mild Traumatic Brain Injury with Social Defeat Stress Alters Anxiety, Contextual Fear Extinction, and Limbic Monoamines in Adult Rats.

Davies DR, Olson D, Meyer DL, Scholl JL, Watt MJ, Manzerra P, Renner KJ, Forster GL - Front Behav Neurosci (2016)

Serotonin (5-HT) measurements 7 days following stress and/or mTBI, including (A) 5-HTP concentration in the ventral hippocampus, (B) 5-HIAA concentration in the dorsal hippocampus, (C) 5-HT activity in the central amygdala, and (D) 5-HT synthesis in the medial prefrontal cortex.∗ Indicates significant difference from all other groups, while ∗ overlying a bar indicates significant difference between individual groups (p < 0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835499&req=5

Figure 4: Serotonin (5-HT) measurements 7 days following stress and/or mTBI, including (A) 5-HTP concentration in the ventral hippocampus, (B) 5-HIAA concentration in the dorsal hippocampus, (C) 5-HT activity in the central amygdala, and (D) 5-HT synthesis in the medial prefrontal cortex.∗ Indicates significant difference from all other groups, while ∗ overlying a bar indicates significant difference between individual groups (p < 0.05).
Mentions: Changes to serotonin function according to treatment were restricted to the hippocampus (dorsal and ventral), the central amygdala, and the medial prefrontal cortex. Alterations in the concentration of 5-HTP were restricted to the ventral hippocampus [Figure 4A; F(3,43) = 4.304, p = 0.010], with the social defeat + mTBI group having significantly higher 5-HTP than all other groups (SNK, p < 0.027). Similarly, the concentration of 5-HIAA was altered in the dorsal hippocampus [Figure 4B; F(3,44) = 4.677, p = 0.006], with the combined treatment of social defeat and mTBI producing higher 5-HIAA concentrations than all other groups (SNK, p < 0.015). Furthermore there was a significant negative correlation between 5-HIAA levels in the dorsal hippocampus and time in open arms of the EPM for social defeat + mTBI group (correlation coefficient = -0.761; p = 0.017). In the central amygdala, serotonergic activity (5-HIAA/serotonin) was significantly different among treatment groups [Figure 4C; F(3,40) = 3.973, p = 0.014], with social defeat + mTBI rats showing higher serotonergic activity than both sham + control (SNK, p = 0.026) and sham + mTBI (SNK, p = 0.019) groups. However, this particular effect appeared to be driven by exposure to social defeat, as changes to central amygdala serotonergic activity were equivalent in all defeated rats with or without mTBI (SNK, p = 0.197). Serotonin synthesis capacity (serotonin/5-HTP) was only affected in the medial prefrontal cortex [Figure 4D; F(3.40) = 3.453, p = 0.025], with exposure to either mTBI, social defeat, or a combination of these two factors causing reductions in the serotonin/5-HTP ratio compared to control + sham rats (SNK, p = 0.046). There were no differences in either 5-HT concentrations in any brain region assayed (Table 1).

Bottom Line: However, this effect was enhanced by the combination of treatments.Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning.The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

View Article: PubMed Central - PubMed

Affiliation: Center for Brain and Behavior Research, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota Vermillion, SD, USA.

ABSTRACT
Mild traumatic brain injury (mTBI) produces symptoms similar to those typifying posttraumatic stress disorder (PTSD) in humans. We sought to determine whether a rodent model of stress concurrent with mTBI produces characteristics of PTSD such as impaired contextual fear extinction, while also examining concurrent alterations to limbic monoamine activity in brain regions relevant to fear and anxiety states. Male rats were exposed to social stress or control conditions immediately prior to mTBI induction, and 6 days later were tested either for anxiety-like behavior using the elevated plus maze (EPM), or for contextual fear conditioning and extinction. Brains were collected 24 h after EPM testing, and tissue from various limbic regions analyzed for content of monoamines, their precursors and metabolites using HPLC with electrochemical detection. Either social defeat or mTBI alone decreased time spent in open arms of the EPM, indicating greater anxiety-like behavior. However, this effect was enhanced by the combination of treatments. Further, rats exposed to both social defeat and mTBI exhibited greater freezing within extinction sessions compared to all other groups, suggesting impaired contextual fear extinction. Social defeat combined with mTBI also had greater effects on limbic monoamines than either insult alone, particularly with respect to serotonergic effects associated with anxiety and fear learning. The results suggest social stress concurrent with mTBI produces provides a relevant animal model for studying the prevention and treatment of post-concussive psychobiological outcomes.

No MeSH data available.


Related in: MedlinePlus